Among radioactive transition metals used in radiopharmaceuticals, Tc-99m is a nuclide most often used in the field of radiodiagnostic imaging because it is advantageous, for example, in that, since the energy of γ-rays emitted by Tc-99m is 141 keV and the half-life of Tc-99m is 6 hours, Tc-99m is suitable for imaging, and that Tc-99m can easily be obtained by means of a 99Mo-99mTc generator. Thus, if a physiologically active substance can be attached to this nuclide without impairing the activity, the resulting compound is considered to be useful as a diagnostic agent.
The various attempts have been made to achieve such attachment, as described below. Transition metal nitride complexes are excellent in stability to hydrolysis. Therefore, when a transition metal nitride complex is subjected to exchange reaction with any of various ligands having a physiological activity, the nitride group of the nitride complex can remain bonded strongly to the metal atom. Accordingly, technetium nitride complexes having various substituents have been proposed. For example, WO 90/06137 discloses diethyl bisdithiocarbamate-Tc nitride complex, dimethyl bisdithiocarbamate-Tc nitride complex, di-n-propyl bisdithiocarbamate-Tc nitride complex and N-ethyl-N-(2-ethoxyethyl) bisdithiocarbamate-Tc nitride complex. Further, WO 89/08657, WO 92/00982 and WO 93/01839 disclose processes for producing a technetium nitride complex which comprises the steps of reacting a polyphosphine as a reducing agent for technetium with technetium oxide, reacting a nitride of a metal or ammonium as a nitrogen source for nitride with the reaction product to convert it to the corresponding nitride, and coordinating a physiologically active monoclonal antibody with this nitride.
In these processes, the choice of the physiologically active ligand is so important that it determines properties of the resulting pharmaceutical. Nevertheless, the metal nitride complex can have various numbers of coordination positions from monodentate to tetradentate and hence is formed in plural forms. Therefore, it has been difficult to obtain a single complex stoichiometrically having a specific physiologically active ligand.
WO 98/27100 discloses that, when a bisphosphine compound is coordinated at two of the four coordination positions of technetium-99m nitride and a bidentate ligand having an electron-donating atom pair is coordinated at the remaining two coordination positions, the bidentate ligand is stoichiometrically coordinated, so that a single technetium-99m nitride heterocomplex can be stably obtained.
JP 2004-505064 A describes a technetium-99m nitride complex wherein a bisphosphine compound is coordinated at two of the four coordination positions thereof and a specific bidentate ligand is coordinated at the remaining two coordination positions thereof. Further, JP 2004-505064 A describes that the technetium-99m nitride complex is markedly accumulated in specific organs such as heart and adrenal glands, and hence is useful for radiodiagnostic imaging. However, it is extremely complicated and difficult to prepare the bisphosphine compound which is an intermediate for preparing the technetium-99m nitride complex.